The transcription factor XBP-1 was identified as a key regulator of the mammalian unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response, which is activated by environmental stressors such as protein overload that require increased ER capacity (D. Ron, P. Walter (2007) Nat Rev Mol Cell Biol 8, 519). XBP-1 is activated by a post-transcriptional modification of its mRNA by IRE-1 alpha, an ER localizing proximal sensor of ER stress (M. Calfon et al. (2002) Nature 415, 92; H. Yoshida, et al. (2001) Cell 107, 881; X. Shen et al. (2001) Cell 107, 893). Upon ER stress, IRE-1 alpha induces an unconventional splicing of XBP-1 mRNA by using its endoribonuclease activity to generate a mature mRNA encoding an active transcription factor, XBP-1s, which directly binds to the promoter region of ER chaperone genes to promote transcription (A. L. Shaffer et al. (2004) Immunity 21, 81; A. H. Lee, et al. (2003) Mol Cell Biol 23, 7448; D. Acosta-Alvear et al. (2007) Mol Cell 27, 53). Mice deficient in XBP-1 display severe abnormalities in the development and function of professional secretory cells, such as plasma B cells and pancreatic acinar cells (N. N. Iwakoshi et al. (2003) Nat Immunol 4, 321; A. H. Lee, et al. (2005) Embo J 24, 4368) and intestinal Paneth cells (Kaser, et al (2008) Cell).
It has previously been shown that XBP-1 plays an important role in modulating toll-like receptor (TLR)-mediated responses and that enhancing XBP-1 activity can amplify the innate immune response. XBP-1 has also plays many other roles. For example, it been shown to activate the UPR, to increase proper protein folding and transport, to increase hepatocyte growth, and to increase plasma cell differentiation. The identification of agents that can be used to increase XBP-1 activity, e.g., by directly binding to and activating IRE-1 would be of great benefit in increasing immune cell activation, e.g., in the context of natural infection, vaccination, and cancer, as well as in promoting XBP-1 activity in other cell types.